Bone metastasis is a frequent, debilitating and essentially incurable cancer complication. More than 70% of patients with advanced breast cancer have metastatic bone disease, leading to severe bone pain, pathological fracture, life-threatening hypercalcemia, spinal cord compression, limited mobility and increased mortality. During bone metastasis, cancer cells and osteoclasts form a vicious cycle so that cancer cells promote osteoclast differentiation and osteoclasts in turn facilitate cancer cell seeding and proliferation in the skeletal environment. Nonetheless, the current understanding of the intricate mechanisms underlying this malicious cycle is still limited, and the existing osteoclast inhibitor drugs confer no survival benefit. Our overarching goal is to discover new and better treatment for cancer bone metastasis that simultaneously suppresses both cancer cell and osteoclast. In December 2014, an inhibitor of Poly (ADP-ribose) polymerase (PARP), Olaparib, was approved by the FDA for treating elapsed BRCA-defective ovarian cancer. Since then, two more PARP inhibitors have also received FDA approval. Several PARP1/2 dual inhibitors are also currently in clinical trials as breast cancer therapy. Despite these clinical efforts on PARP inhibitors in cancer treatment, little is known about the roles of PARPs in metastasis. Moreover, it is unclear whether and how different PARP family members display distinct functions. In our preliminary studies, we have found that PARP2 loss, but not PARP1 loss, promotes bone metastasis by acting in both osteoclast and tumor cell to enhance osteoclastogenesis; olaparib treatment exacerbates bone metastasis in a manner that is dependent on modifiers such as BRCA status and drug resistance. We hypothesize that PARP2 is a powerful dual suppressor of bone metastasis by regulating key targets in osteoclast and tumor cell to synergistically impede breast cancer malignancy. Here we propose to perform a series of comprehensive analyses to test this hypothesis, combining genetic and pharmacological, gain- and loss-of-function, in vitro and in vivo strategies. In Aim 1, we will determine how PARPs in osteoclast regulate bone metastasis. In Aim 2, we will determine how PARPs in cancer cell regulate bone metastasis. In Aim 3, we will elucidate the molecular and biochemical mechanisms for PARP regulation of bone metastasis by identifying and functionally characterizing key PARP targets. This investigation is highly significant and clinically relevant because it will identify PARP2 as a novel dual suppressor of breast cancer bone metastasis, uncover potential deleterious yet context-dependent effects of current PARP1/2 dual inhibitor cancer drugs to exacerbate skeletal metastasis, reveal important functional distinctions between PARP2 and PARP1, suggest PARP1-specific inhibitors as possibly safer options, highlight the exciting therapeutic potential of PARP2 activation to mitigate breast cancer bone metastasis, and provide crucial insights for personalized medicine and tailored treatment to better design and utilize PARP inhibitors as cancer drugs.